An unprecedented oxidative wagner - Meerwein transposition

Article abstract of DOI:10.1021/ol902000j

An oxidative Wagner - Meerwein transposition Involving different functionalities mediated by a hypervalent Iodine reagent has been accomplished. The strategy fits within the concept of "aromatic ring umpolung" and allows rapid access to highly functionali

Full text of DOI:10.1021/ol902000j

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4756-4759
An Unprecedented Oxidative
Wagner-Meerwein Transposition
Kimiaka C. Gue´rard, Cle´ment Chapelle, Marc-Andre´ Giroux, Cyrille Sabot,
Marc-Andre´ Beaulieu, Nabil Achache, and Sylvain Canesi*
Laboratoire de Me´thodologie et Synthe`se de Produits Naturels, UniVersite´ du Que´bec
a` Montre´al, C.P. 8888, Succ. Centre-Ville, Montre´al, H3C 3P8, Que´bec, Canada
canesi.sylVain@uqam.ca
Received August 27, 2009
ABSTRACT
An oxidative Wagner-Meerwein transposition involving different functionalities mediated by a hypervalent iodine reagent has been accomplished.
The strategy fits within the concept of “aromatic ring umpolung” and allows rapid access to highly functionalized cores.
One of the most remarkable transformations in organic
synthesis is probably transposition. Indeed, this process
allows the transformation of a simple structure into a variety
of more complex motifs. The Wagner-Meerwein and
pinacolic transpositions1 are among the most well-known of
these rearrangements. Moreover, electron-rich aromatic
compounds, such as phenols and their derivatives, normally
react as nucleophiles. However, an oxidative activation2-4
can transform these aromatics into very reactive electrophilic
species 2, which may be intercepted with appropriate
nucleophiles in synthetically useful yields. An indication of
how this objective can be achieved is apparent in the work
of Kita,2 who has shown that phenols may be activated under
the influence of hypervalent iodine reagents such as iodo-
benzene diacetate (DIB), an environmentally benign and
inexpensive reagent. This reaction is generally best performed
in solvents such as hexafluoroisopropanol (HFIP).2 If one
considers the behavior of the electrophilic species 2, this
reversal of reactivity may thus be thought of as involving
“aromatic ring umpolung”.5,6 This concept provides new
strategic opportunities in synthetic chemistry, by extension
of several well-known reactions in aliphatic chemistry to
aromatic chemistry. An oxidative extension of a transposition
could lead rapidly to a plethora of applications in total
synthesis. In this paper, we illustrate an extension to the
Wagner-Meerwein rearrangement to phenols that takes place
via an oxidative process (Figure 1).
As an initial investigation, we decided to test the feasibility
of an oxidative transposition. In this purpose, the corre-
sponding phenols 4 have been oxidized to generate the
(3) (a) Pelter, A.; Drake, R. A. Tetrahedron Lett. 1988, 29, 4181. (b)
Quideau, S.; Looney, M. A.; Pouyse´gu, L. J. Org. Chem. 1998, 63, 9597.
(c) Ozanne-Beaudenon, A.; Quideau, S. Angew. Chem., Int. Ed. 2005, 44,
7065. (d) Ciufolini, M. A.; Canesi, S.; Ousmer, M.; Braun, N. A.
Tetrahedron 2006, 62, 5318. (e) Ciufolini, M. A.; Braun, N. A.; Canesi,
S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 24, 3759. (f) Be´rard,
D.; Jean, A.; Canesi, S. Tetrahedron Lett. 2007, 48, 8238. (g) Jean, A.;
Cantat, J.; Be´rard, D.; Bouchu, D.; Canesi, S. Org. Lett. 2007, 9, 2553. (h)
Pouyse´gu, L.; Chassaing, S.; Dejugnac, D.; Lamidey, A. M.; Miqueu, K.;
Sotiropoulos, J. M.; Quideau, S. Angew. Chem., Int. Ed. 2008, 47, 3552.
(i) Be´rard, D.; Racicot, L.; Sabot, C.; Canesi, S. Synlett 2008, 1076. (j)
Pouyse´gu, L.; Marguerit, M.; Gagnepain, J.; Lyvinec, G.; Eatherton, A. J.;
Quideau, S. Org. Lett. 2008, 10, 5211. (k) Zhdankin, V. V.; Stang, P. J.
Chem. ReV. 2008, 108, 5299, and citations therein. (l) Mendelsohn, B. A.;
Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett.
2009, 11, 1539. (m) Quideau, S.; Lyvinec, G.; Marguerit, Bathany, K.;
Ozanne-Beaudenon, A.; Bufeteau, T.; Cavagnat, D.; Chenede, A. Angew.
(1) (a) Fittig, R. Justus Liebigs Ann. Chem. 1860, 114, 54. (b) Wagner,
G. J. Russ. Chem. Soc. 1899, 31, 690. (c) Meerwein, H. Justus Liebigs
Ann. Chem. 1914, 405, 129.
(2) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987,
52, 3927. (b) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684. (c)
Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn, J. J.
Org. Chem. 1996, 61, 5854. (d) Kita, Y.; Gyoten, M.; Ohtsubo, M.; Tohma,
H.; Takada, T. Chem. Commun. 1996, 1481. (e) Takada, T.; Arisawa, M.;
Gyoten, M.; Hamada, R.; Tohma, H.; Kita, Y. J. Org. Chem. 1998, 63,
7698. (f) Arisawa, M.; Utsumi, S.; Nakajima, M.; Ramesh, N. G.; Tohma,
H.; Kita, Y. Chem. Commun. 1999, 469. (g) Akai, S.; Kawashita, N.; Morita,
N.; Nakamura, Y.; Iio, K.; Kita, Y. Heterocycles 2002, 58, 75. (h) Dohi,
T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka,
H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787. (i)
Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073
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10.1021/ol902000j CCC: $40.75
Published on Web 09/21/2009
 2009 American Chemical Society

such acetal functionality has never been reported as of this
writing. A potential mechanism is described in Scheme 1.
Scheme 1. Oxidative Transposition-Acetal Tandem Process
Figure 1. Oxidative migration.
electrophilic species 5. This latter promotes the desired
rearrangement leading to compounds 6 in useful yields
(33-67%). Formation of compound 4 is easily obtained in
high yield by addition of an excess of allyl Grignard on the
corresponding 4-hydroxyphenones. Allyl groups have been
chosen because they are known to be very good migrating
groups involving a potential concerted mechanism during
the transition state. It should be noted that the direct migration
of the allyl group is not excluded (Figure 2).
To broaden the scope of this reaction, other potential
migrating groups have been tested with sp2 carbons such as
an alkene or an aryl. These groups are easily introduced by
a 1-2 addition on the corresponding ketone. The formation
of the corresponding dienone 15 is observed, probably via
the formation of an arenium intermediate 14. Obtaining a
structure such as 12 or 15 represents a synthetic challenge
due to the complexity associated with generating a quaternary
carbon center connected to four sp2 carbons. Indeed, the
formation of such architecture using conventional chemistry
could become problematic (Scheme 2).
Figure 2. Oxidative allylic migration.
An important aspect of this strategy is the ability to
transform quickly an inexpensive and simple phenol into a
highly functionalized core containing a prochiral dienone, a
quaternary carbon center connected to several sp2 carbons,
and spectator functionalities could be present on the side
chain. To exemplify this transformation, different phenols
containing an allyl group have been oxidized. A summary
of representative experiments appears in Table 1.
Scheme 2.
sp2 Carbon Migration
Table 1. Oxidative Allylic Transposition
To exemplify this transformation, different phenols con-
taining an aryl group have been oxidized. The skeleton
entry
R
R1
R2
yield
a
b
c
d
e
H
H
Me
H
H
Me
H
H
H
Me
H
62
67
63
37
33
(4) (a) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Swenton,
J. S. J. Org. Chem. 1992, 57, 2135. (b) Braun, N. A.; Ciufolini, M. A.;
Peters, K.; Peters, E. M. Tetrahedron Lett. 1998, 39, 4667. (c) Quideau,
S.; Looney, M. A.; Pouyse´gu, L. Org. Lett. 1999, 1, 1651. (d) Braun, N. A.;
Bray, J.; Ousmer, M.; Peters, K.; Peters, E. M.; Bouchu, D.; Ciufolini, M. A.
J. Org. Chem. 2000, 65, 4397. (e) Scheffler, G.; Seike, H.; Sorensen, E. J.
Angew. Chem., Int. Ed. 2000, 39, 4593. (f) Ousmer, M.; Braun, N. A.;
Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123,
7534. (g) Quideau, S.; Pouyse´gu, L.; Oxoby, M.; Looney, M. A. Tetrahedron
2001, 57, 319. (h) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.;
Ciufolini, M. A. Tetrahedron Lett. 2002, 43, 5193. (i) Drutu, I.; Njardarson,
J. T.; Wood, J. L. Org. Lett. 2002, 4, 493. (j) Canesi, S.; Bouchu, D.;
Ciufolini, M. A. Angew. Chem., Int. Ed. 2004, 43, 4336. (k) Quideau, S.;
Pouyse´gu, L.; Deffieux, D. Curr. Org. Chem. 2004, 8, 113. (l) Canesi, S.;
Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175. (m) Nicolaou, K. C.;
Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem. 2007, 119, 4016. (n)
Quideau, S.; Pouyse´gu, L.; Deffieux, D. Synlett 2008, 467. (o) Liang, H.;
Ciufolini, M. A. J. Org. Chem. 2008, 4299. (p) Giroux, M. A.; Gue´rard,
K. C.; Beaulieu, M. A.; Sabot, C.; Canesi, S. Eur. J. Org. Chem. 2009,
3871.
CH2CHdCH2
Me
Me
CH2OTBS
In addition, a noteworthy transformation is observed by
oxidation of the silicon-ether 7 leading to the acetal 10 in
58% yield. Indeed, the alkene moiety present in the side chain
would react with the potential cation 8, and a C-C bond
fragmentation would lead to intermediate 9 that would be
trapped by the acetic acid released during the reaction to
afford 10. This transformation is similar to an oxidative
pinacol/acetalization tandem process. It should be noted that
Org. Lett., Vol. 11, No. 20, 2009
4757

generated should have different applications in total synthesis,
due to the numerous natural products containing such core,
such as the Amaryllidaceae alkaloids family.7 A summary
of representative experiments appears in Table 2.
are observed. In addition, an oxidation of compound 24
produces a noteworthy ring contraction leading to 25 in 53%
yield. These results demonstrate the large potential of this
novel transformation and its potential application in synthesis
(Scheme 4).
Table 2. Migration of Aryl Groups
Scheme 4. Migration of Alkyl Groups
entry
R
R1
yield
a
b
c
H
Me
H
Me
Me
Et
51
34
35
This strategy can also be used with bicyclic phenols to
produce the corresponding dienone skeleton (Scheme 3).
The reaction with allyl groups can be extended to
compounds 26 and 29, via an unprecedented 1,3-allyl shift,
probably due to a concerted mechanism involving an
intermediate such as 27. This transformation could be
assimilated to an unreported homo-Wagner-Merweein pro-
cess. This strategy leading to such cores could be helpful to
produce rapidly elaborated structures (Scheme 5).
Scheme 3. Oxidation of Bicyclic Phenols
Scheme 5. Homo-Wagner-Meerwein Transposition
To explore the scope and limitations of this reaction, we
proceeded to extend the feasibility of this rearrangement to
simple alkyl groups. In this purpose, oxidations of acyclic
and bicyclic phenols have been accomplished. As expected,
during the oxidation of compound 20 the migration of the
butyl group is very predominant; only a small amount of
methyl migration is observed (∼5%). In addition, oxidation
of phenol 22 leads to compound 23, in 41% yield. It should
be noted that this oxidative process seems to occur as a
regular rearrangement applicable to a large scope of aryl,
allyl, and alkyl groups. Indeed, the same rules as the ones
applying to a conventional Wagner-Meerwein transposition
This transformation with compound 26 occurs in low yield;
further investigation has demonstrated that the corresponding
aldehyde 28 was not very stable in these conditions. To solve
this problem, the corresponding aldehyde generated in situ
has been transformed into a more stable functionality. Indeed,
the transposition/acetalization process described in Scheme
2 has been used on compound 31 to produce a mixed acetal
34 in 42% yields. This later is associated with a small amount
of aldehyde 28 (5-10%) (Scheme 6).
(5) The concept of “umpolung” chemistry has been discovered by E. J.
Corey and D. Seebach: (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975,
40, 231. (b) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239.
(6) (a) Be´rard, D.; Giroux, M. A.; Racicot, L.; Sabot, C.; Canesi, S.
Tetrahedron 2008, 7537. (b) Sabot, C.; Be´rard, D.; Canesi, S. Org. Lett.
2008, 10, 4629. (c) Sabot, C.; Commare, B.; Nahi, S.; Duceppe, M. A.;
Gue´rard, K. C.; Canesi, S. Synlett 2008, 3226. (d) Gue´rard, K. C.; Sabot,
C.; Racicot, L.; Canesi, S. J. Org. Chem. 2009, 74, 2039. (e) Sabot, C.;
Gue´rard, K. C.; Canesi, S. Chem. Commun. 2009, 2941.
Scheme 6. Oxidative 1,3-Allyl Shift
(7) (a) Ochi, M.; Otsuki, K.; Nagao, K. Bull. Chem. Soc. Jpn. 1976,
3363. (b) Likhitwitayawuld, K.; Angerhofer, C. K.; Chai, H.; Pezzuto, J. M.;
Cordell, G. A.; Ruangrungsi, N. J. Nat. Prod. 1993, 56, 1331. (c) Lewis,
J. R. Nat. Prod. Rep. 1998, 15, 107. (d) Abdel-Halim, O. B.; Morikawa,
T.; Ando, S.; Matsuda, H.; Yoshikawa, M. J. Nat. Prod. 2004, 67, 1119.
(e) Szlavik, L.; Cyuris, A.; Minarovits, J.; Forgo, P.; Molnar, J.; Hohmann,
J. Plant Med. 2004, 70, 871. (f) Jin, Z. Nat. Prod. Rep. 2005, 22, 111.
To broaden the scope of this novel transposition, the allylic
segment has been substituted by a propargylic group.
4758
Org. Lett., Vol. 11, No. 20, 2009

Oxidation of compound 33 produces the desired allenic
moiety with a noteworthy global yield of 72% and in a ratio
close to (3/2) between the acetal 34 and the aldehyde 35.
Treatment of compound 34 with TFA leads quantitatively
to the aldehyde 35. This process seems to occur more
efficiently with a propargylic group than an allyl group. This
aspect could be rationalized by the linear geometry of the
sp carbon center that would be more oriented to interact with
the phenoxonium ion generated (Scheme 7).
In addition, this transposition can be accomplished on the
bicyclic phenol 40 to produce the dienone 41 in 52% yield.
The introduction of bromines in ortho position is necessary
to force the allyl group during the oxidative process to react
only in para position. Moreover, we suppose that the
migration of the allyl group should occur stereospecifically
with a retention of configuration, due to the concertness of
the mechanism involved (Scheme 9).
Scheme 9. Carbocyclization-Fragmentation Process
Scheme 7. Formation of Allenic Moiety
In summary, an unprecedented and oxidative transposition
process allows a rapid access to highly functionalized
synthons containing a dienone, a quaternary carbon center
directly connected to several sp2 carbons. This transformation
provides new strategic opportunities in the chemical synthesis
of substances and results in ongoing investigations; their
applications will be disclosed in due course.
We have also been interested to trap the corresponding
oxonium generated on the side chain with an intramolecular
nucleophile that does not need the presence of acetic acid in
the medium. The oxidation of compound 36 leads to the
acetal 39. An interesting aspect of this reaction is the
spectacular rearrangement observed during the umpolung
activation. Indeed, a simple phenol containing an ether
functionality is redesigned in only one step into a highly
elaborated core containing several functionalities present on
almost each carbon (Scheme 8).
Acknowledgment. Acknowledgment is made to the
Donors of the American Chemical Society Petroleum
Research Fund (ACS PRF) for support of this research. We
are also very grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Canada Founda-
tion for Innovation (CFI), the provincial government of
Quebec (FQRNT), and to Boehringer Ingelheim (Canada)
Ltd. for their financial support.
Scheme 8
.
Oxidative Transposition/Acetalization Tandem
Process
Supporting Information Available: Experimental pro-
cedures and spectral data of key compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL902000J
Org. Lett., Vol. 11, No. 20, 2009
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